Impact of Interventions on Medication Adherence in Patients With Coexisting Diabetes and Hypertension

ABSTRACT Background The coexistence of diabetes and hypertension is prevalent due to shared risk factors. Pharmacological treatment has been reported to be effective in managing both conditions. However, treatment effectiveness depends on the extent to which a patient adheres to their treatment. Poor adherence to long‐term treatment for chronic diseases is a growing global problem of significant magnitude. Several interventions have been developed to help improve medication adherence in patients with coexisting diabetes and hypertension. This review aimed to determine the characteristics of these interventions and their impact on medication adherence. Methods A systematic review of the literature was conducted using the PRISMA guidelines and registered in the PROSPERO International Registry of Systematic Reviews. Studies were searched in the databases CINAHL, Embase and Medline to identify relevant articles published during 2012–2023. The search concepts included ‘medication adherence’, ‘hypertension’, ‘diabetes’ and ‘intervention’. Studies were included if they were in English and evaluated the impact of an intervention aimed at promoting adherence to medications for both diabetes and hypertension. Results Seven studies met the inclusion criteria, with five demonstrating a statistically significant improvement in medication adherence. Of the five studies that improved medication adherence, four were multifaceted and one was a single‐component intervention. All successful interventions addressed at least two factors influencing non‐adherence. Patient education was the foundation of most of the successful interventions, supported by other strategies, such as follow‐ups and reminders. Conclusion Multifaceted interventions that also included patient education had a positive impact on medication adherence in patients with coexisting diabetes and hypertension. Improving adherence in patients with coexisting diabetes and hypertension requires a multipronged approach that considers the range of factors impacting medication‐taking. Patient or Public Contribution This systematic review provides comprehensive insights into the benefits of patient‐centred approaches in intervention development and strengthening. Such patient involvement ensures that medication adherence interventions are more relevant, acceptable and effective, ultimately leading to better health outcomes and more meaningful patient engagement in healthcare research.

diabetes leads to the accumulation of glucose in the bloodstream, which can damage blood vessels and kidneys, resulting in high blood pressure [4,5].
Pharmacological treatment decreases complications and premature death associated with diabetes and hypertension [7,8].However, treatment effectiveness is highly dependent on the patient's level of medication adherence [9].Medication adherence is generally defined as 'the process by which patients take their medications as prescribed' [10].Due to suboptimal treatment adherence, the pharmacological effect of medications seen in randomized-controlled trials can be less pronounced in realworld settings [11,12].
Poor adherence to medication is a worldwide public health concern, particularly for chronic conditions, with estimated general non-adherence rates at approximately 50% [13].Poor adherence is strongly associated with an increased economic and resource burden at both the health system and the patient level [6].Various barriers to adherence have been identified and these include forgetfulness, poor communication between healthcare provider and patient, low health literacy and lack of conviction on the need for treatment [2,14].
Patients with coexisting diabetes and hypertension face numerous challenges to their health, as these conditions affect different organ systems, which results in them needing two or more medications [2,3,6].Being on multiple medications increases the risk of undesirable side effects, adverse reactions and increased medical expenditure [3,8].These risks also lead to poor adherence, especially in patients with limited knowledge of their condition [3,6,15].Globally, adherence to medication therapy ranges between 36% and 93% in patients with coexisting diabetes and hypertension [8].
Good medication adherence is strongly associated with a high level of disease control [6,11].The level of disease control for hypertension and diabetes is reported to be low in patients with coexisting diabetes and hypertension [6].For instance, Song et al. [16] reported a control rate of 40% and 41% for hypertension and diabetes, respectively, among patients aged 20 years and older with coexisting diabetes and hypertension at a hospital in China.The World Health Organization (WHO) identifies improving medication adherence as a more direct way to influence patient outcomes than addressing treatment improvements [17].
Addressing medication adherence for both conditions collectively is vital as the two conditions are closely linked such that each condition can potentially worsen the other [4,5].For instance, uncontrolled hypertension can exacerbate diabetesrelated complications such as kidney disease and neuropathy [4,5].On the other hand, poorly controlled diabetes increases vascular damage, making hypertension harder to control [4,5].Addressing medication adherence for both conditions collectively can ensure a more coordinated and effective approach to patient care that not only leads to better health outcomes but also cost-effective treatment plans [18].
Medication non-adherence is multifactorial and involves patients, healthcare providers, health systems, families and communities [8,15].Determinants of adherence are well established and several interventions have been developed to improve medication adherence in a range of diseases [19].Several interventions have been designed to help patients manage their medication regimens more effectively, such as dispensing aids (e.g., pill boxes and webster packs) [20][21][22].Digital innovations have also expanded the range of interventions through the development of mobile health applications and wearable devices that remind patients to take their medication [15].Other interventions that have been developed target motivating and educating patients such as incentive payment, group sessions, patient education and follow-up [15,19].These interventions have not been effective in all cases, and importantly, are not sustainable long term.For instance, incentives have been successful in improving medication adherence, but the effect was not sustainable after the incentives were withdrawn [23].Similarly, many interventions require frequent communication and active monitoring, which may be impractical for most healthcare providers [15,19].
Despite the increased incidence of coexisting diabetes and hypertension, most studies report on interventions to address medication adherence in diabetes and hypertension individually.This study will contribute to the body of knowledge on the impact of interventions on medication adherence in patients with coexisting diabetes and hypertension.To the best of our knowledge, no systematic review has focused on the impact of interventions on medication adherence in patients with coexisting diabetes and hypertension.Therefore, this systematic review aimed to 1. investigate the characteristics of interventions used to improve medication adherence in patients with coexisting diabetes and hypertension and 2. determine the impact of these interventions on improving medication adherence in patients with coexisting diabetes and hypertension.

| Methods
A systematic review of the literature was conducted using the PRISMA guidelines and registered in the PROSPERO International Registry of Systematic Reviews (registration number-CRD42023423096).

| Literature Search
We performed a literature search to identify research articles that assessed the impact of interventions on adherence to diabetes and hypertension medication in patients with coexisting diabetes and hypertension.Studies were searched in the following databases: CINAHL, Embase and Medline.Additional studies were identified through reference searching.Search terms included a combination of both controlled vocabulary and keywords such as 'medication adherence', 'hypertension', 'diabetes' and 'intervention'.The complete search strategy is provided in Supporting Information S2: File A.

| Eligibility Criteria
The search strategy was limited to studies published in English from June 2012 to December 2023 (inclusive).We limited the time of search to 2012-2023 because the Ascertaining Barriers to Compliance (ABC) taxonomy [10] for medication adherence that promotes consistency in taxonomy and methods used in studies addressing medication adherence was published in April 2012.Eligible studies fulfilled the following inclusion criteria: (1) intervention addressed medication adherence to therapeutic medication in both hypertension and diabetes, (2) medication adherence was one of the study outcomes and (3) published from June 2012 to December 2023 (inclusive).Studies that focused on medication adherence to prophylactic medication were excluded.Full texts were reviewed using the eligibility criteria mentioned above.Any disagreement between the two authors (P.T.M. and B.B.C.) was resolved by the third author (P.A.), and discussion until consensus was reached.

| Data Extraction and Analysis
Covidence is a web-based screening and data extraction tool for systematic reviews [24].Data extraction was performed using a predesigned form generated through Covidence, which was edited to align with the review.We extracted information about (1) the author(s)/publication year, (2) study type, (3) country, (4) funding, (5) study setting, (6) type of intervention, (7) duration of intervention, (8) interventionist, ( 9) training of interventionist, (10) description of intervention, (11) nonadherence determinants addressed by intervention, (12) adherence measuring tool and ( 13) effect of intervention on medication adherence.One author (P.T.M.) screened all studies based on the titles and abstracts and a second author (P.A.) screened 10% of the articles to check for any disagreements.
Interventions were defined as all strategies designed to improve medication adherence as either a primary or secondary outcome.
For each study included in the review, we identified the determinants of non-adherence addressed by the intervention against the WHO classification: socioeconomic factors, healthcare team-and system-related factors, therapy-related factors, patient-related factors and condition-related factors [25].In this review, medication adherence was defined as the degree to which individuals follow their prescribed medication regimen.We compared the definition used in the reviewed studies to the ABC taxonomy [10].The ABC taxonomy defines medication adherence as 'The process by which patients take their medication as prescribed' and classifies the process into three phases, namely, initiation, implementation and discontinuation (Figure 1) [10].Finally, we analysed additional outcomes linked to diabetes and hypertension management that were assessed in the studies.

| Quality Assessment
The quality of studies was rated against the Covidence template for quality assessment (Risk of Bias), which is based on the Cochrane Risk of Bias version 1 tool [26].Domains were scored as high (+) (good methodological safeguards to prevent bias), low (−) (poor methodological safeguards to prevent bias or unsure (?) (unclear methodological safeguards to prevent bias).Two independent authors (P.T.M. and B.B.C.) assessed all studies to determine the risk of bias.Any disagreement between the authors was resolved by the third author (P.A.).

| Study Selection
The literature search identified 2657 citations and one additional study was identified through reference searching, as illustrated in Figure 2. Of these, 67 appeared to meet the inclusion criteria and were retrieved in full text.Seven articles met the study inclusion criteria and were analysed.

| Quality Appraisal
Four studies with a positive score on at least four domains were recorded as high-quality studies, whereas three studies were classified as low quality as illustrated in Table 1.There was limited or no information on the blinding of people analysing the outcomes from intervention allocation in the studies reviewed.Therefore, the reviewed studies received ratings indicating either a 'low' or 'unsure' level of safeguarding against bias on blinding of outcome assessment.
Inclusion criteria varied between studies and included age, diabetes or hypertension type, duration since diagnosis of both conditions and duration on medication.The minimum age for four studies [3,6,11,15] was reported as 18 years and only two studies reported a maximum age limit of 60 [11] and 65 [6] years.Only Contreras-Vergara et al. [11] limited the primary diagnosis based on hypertension type to systemic arterial hypertension and five [3,6,8,11,15] studies limited the diabetes type to type 2.
One study used duration since being diagnosed with both conditions [3] and another used duration on pharmacological treatment [8] as inclusion criteria.Disease control and clinical variables were used as inclusion criteria in three [2,6,15] of the studies, whereas the other four did not specify these [3,8,11,12].For example, Moorhead et al. [15] and Wang et al. [6] recruited participants with uncontrolled hypertension and diabetes, whereas Malik et al. [2] recruited participants who had HbA1c ≥ 7% and blood pressure > 140/90 at diagnosis.The smallest study population had n = 50 [8], whereas the largest assessed 3602 [12] prescription records.Table 2 presents the characteristics of the included studies.

| Medication Adherence
Generally, all studies regarded medication adherence as the extent to which a patient follows a therapeutic regimen.None of the studies in this review used the medication adherence taxonomy or referred to the three adherence phases [10].Even though all studies used the word 'adherence' to describe medication-taking behaviour, some (n = 4) [2,6,11,15] also used terms such as 'compliance' and 'noncompliance'.
To measure medication adherence, most studies (n = 6) [2,3,6,8,11,12] used indirect methods of measuring medication adherence, with two [8,12] using objective methods such as pill counts and four [2,3,6,11] using subjective methods such as patient questionnaires (full details about the methods of measuring medication adherence are provided in Appendix S1).The two studies [8,12] that used objective methods did not report a statistically significant improvement in medication adherence.
[6] recruited one pharmacist with 10 years of professional experience to evaluate medication adherence.One study [12] evaluated the impact of an intervention on patients' medication adherence, where the intervention was delivered to the interventionist (physicians).All other studies delivered an intervention directly to the patient participants and evaluated the impact of the intervention on patient outcomes.Specifically, Malik et al. [2] focused on both training interventionists and delivering the intervention to the patient participants, and Contreras-Vergara et al. [11] used a trained pharmacist to deliver the intervention to the intervention group and physicians to deliver regular education to the control group participants.

| Characteristics of Interventions Reporting Improved Medication Adherence
Four [2,3,6,11] out of the five [2,3,6,11,15] studies that showed a statistically significant improvement in medication adherence used multifaceted interventions.Pharmacists were the interventionists in these four studies.Training of interventionist [2,11] or use of experienced interventionist [6] was reported in 60% of the successful studies.The factors related to non-adherence that were targeted by the interventions showed a similar pattern.All successful interventions addressed at least two WHO dimensions of factors influencing non-adherence, with the common ones being patient-related [2,3,6,11,15], healthcare team/system-related [2,3,6,11,15] and therapyrelated factors [2,3,6,11].
Patient education was the cornerstone in 80% [2,3,6,11] of the successful interventions.All successful interventions [2,3,6,11,15] focused mainly on delivering the intervention to the patient, with a particular emphasis on patient empowerment.
The common issue addressed under the healthcare team/ system-related dimension was improved communication between healthcare practitioners and patients and the training of interventionists.Interventions with a prolonged or consistent interaction between healthcare professionals and patients reported a statistically significant improvement in medication adherence.For example, Malik et al. [2] reported that the participants met with the pharmacists every 15 days for 6 months, whereas Wang et al. [6] reported a meet-up every week, daily WeChat (Mobile messaging application) account access and continuous follow-ups every 2 weeks.

| Additional Outcomes Assessed
Six [2,3,6,8,11,15] of the studies assessed additional outcomes and these included blood pressure, fasting plasma glucose (FPG), glycated haemoglobin (HbA1c), systolic blood pressure (SBP), diastolic blood pressure (DBP) and patient knowledge.All multifaceted [2,3,6,8,11] interventions assessed more than three additional outcomes linked to diabetes and hypertension management such as blood pressure and reported a significant improvement in at least three outcomes.This was not the same for the two single-component interventions, as only Moorhead et al. [15] assessed risk of overdosing as the only additional outcome.Table 4 summarizes the additional outcomes linked to hypertension and diabetes management assessed in the included studies.

| Discussion
This review identified a small number of studies that focused on medication adherence interventions in patients with co-existing diabetes and hypertension.However, a majority of the interventions reported in these studies demonstrated a significant positive impact on medication adherence.Most of the successful interventions used a multifaceted strategy that targeted both educational and behavioural aspects of adherence.This is in line with previous literature and suggests that multifaceted interventions are more effective than single-component interventions, as they appear to target both intentional and nonintentional medication adherence [27,28], and more than one factor impacting medication-taking.Similarly, Sapkota et al. [28] found that multifaceted interventions were more successful in improving medication adherence than single strategies in Good adherence-Pill count between 80% and 110%.
• Face-to-face interviews to educate patients on their disease and treatment.
• Pharmacotherapeutic plan tailored to patient needs.
• Calendar to prevent forgetfulness.
• Face-to-face consultations educating patients on their condition and treatment.
• Patients received wallet cards with updated lists of their medications.
• Recommendations for follow-up care.
• Regular  Access screen: Low sum of ranksimproved access to medication.
tailored to their needs and were educated on their condition and medication.
• Patients were given patient kits with disease brochures, BP and glucose monitoring cards and diet charts.

1734.5
Recall screen:  patients with diabetes.In contrast, a study that assessed the impact of multifaceted interventions to support medication adherence after stroke did not report a positive impact [29].However, this could be attributed to the high initial adherence in the study, leaving little room for further improvement.
We found that all successful interventions addressed patientrelated and healthcare professional/team determinants of nonadherence.These findings underscore the importance of a patient-centred approach to fostering medication adherence and maintaining a therapeutic alliance to support medicationtaking.A strong therapeutic alliance between the patient and the healthcare professional has been associated with improved medication adherence, as it leads to a more personalized approach to healthcare.The strength of a therapeutic alliance is reliant on both the patient and the healthcare professional [30,31], as well as on effective communication [30] Continuous communication between the patient and the health service provider was a consistent component of most of the successful interventions identified in this review.Paterick et al. [32] highlighted the importance of a continuous connection between health professionals and patients in the effective management of chronic diseases.Similarly, Williams et al. [33] emphasized that the flow of information between patients and health professionals should be consistent with the progression of the chronic disease.These findings suggest that continuous communication must be utilized in medication adherence interventions, as it could lead to more favourable outcomes and reinforce the sustainability of the intervention.
There was strong evidence for a positive effect of interventions using patient education as a strategy for improving patient adherence in this review.The cornerstone for medication adherence is patient education.Patient education enhances selfmanagement, which has long been recognized as an effective technique for improving medication adherence [34].Various studies have associated enhanced patient education with improved medication adherence [30,31,35].
Moreover, all successful interventions focused mainly on empowering the patient, with a few also focusing partly on empowering the healthcare professional.Only De Leon et al. focused mainly on empowering the healthcare care providers to provide better care but did not report a significant change in medication adherence.Research evidence suggests that effective interventions should adopt a patient-centred approach as a foundation for developing new, and enhancing existing, adherence interventions [32,36].A greater improvement in medication adherence can be expected from empowering patients to take on an active role in their healthcare management.However, this approach should be complemented by empowering healthcare providers to support and guide patients effectively.
Training of interventionists has been demonstrated to improve the consistency and effectiveness of the intervention, which leads to better patient engagement and adherence [37].For example, a review that examined interventions addressing adherence to medication among adults with chronic conditions reported that training interventionists before they deliver • WeChat account where participants could ask pharmacists questions.
• Follow-up by telephone every two weeks.
a Medication adherence combined for diabetes and hypertension.
interventions was associated with better outcomes in medication adherence [20].The evidence provided in this review offers additional support for training interventionists.Pharmacists were the most common interventionists in the successful interventions identified.Pharmacists are experts in pharmacotherapy and patient education, and therefore best placed to deliver interventions aimed at promoting medication adherence [35].
All studies that explored patient outcomes in addition to medication adherence, such as blood pressure and blood glucose, reported significant changes in at least one of the variables assessed.This suggested that interventions targeting medication adherence could also lead to other improved health outcomes associated with improved medication-taking.Lehmann et al. [38] emphasized the strength of the association between medication adherence and clinical outcomes.Several studies have associated improved clinical outcomes with improved medication adherence [3,39,40].However, in this review, this association was inconsistent.The inconsistency could be attributed to other factors, such as lifestyle.Given that both these conditions are lifestyle-related, these inconsistencies call for a more precise method of how medication adherence together with other factors such as lifestyle modification impact blood pressure and glucose control.
Despite the positive impact of the interventions, it is possible that there were factors in the studies that, if considered, may have further improved medication adherence.Duration since diagnosis is one such factor.Ofori-Asenso et al. [41] examined statin adherence in patients aged ≥ 65 years and reported that the risk of non-adherence was highest during the first year of starting treatment [41].Hence, when evaluating the impact of interventions on medication adherence, it is important to take into account when the intervention is being delivered in the patient's medication-taking journey.
It was noticeable that only Soto et al. [8] included social support and none of the studies addressed cost-related issues.Social support is a significant influencer of medication adherence as it promotes psychological comfort and influences materialistic support [35,42].Cost-related non-adherence is a consistently reported challenge, particularly in developing countries [42][43][44].
Decreasing out-of-pocket costs through strategies such as decreasing co-payments and referring patients to state-or company-based assistance plans has the potential to combat cost-related non-adherence [12,43,44].
This review identified several limitations within the included studies, which should be taken into account when interpreting the findings.Although blinding participants and interventionists in face-to-face delivered intervention studies is impossible, blinding of outcome assessments can enhance the quality of the studies.However, the majority of articles in this review lacked sufficient information on blinding of outcome assessment.The combining of adherence without specifying medication adherence with regard to hypertension or diabetes obscures the impact of the interventions on individual conditions.Another key limitation of most studies included was the reliance on selfreporting.Although self-reported data can provide valuable insights into patients' experiences and behaviours, there are potential concerns regarding the accuracy and reliability of these data.
Interestingly, all studies [8,12] that used objective methods of measuring adherence in this review did not report a significant improvement in medication adherence.However, De Leon et al. commented on the fact that they did not know whether the control group received any health information technology support and Soto et al. did not have a control group that served as a benchmark to measure the effect of an intervention.Due to the limitations of the study designs and available data, it is challenging to draw a definitive connection between objective methods of measuring adherence and the adherence results observed.
Future research could benefit from addressing these limitations by using blind data analysts, both objective and subjective measures of adherence and being disease-specific when addressing/reporting adherence in patients with both hypertension and diabetes.Additionally, interventions should aim to target all five WHO determinants of non-adherence [25], as adherence determinants are likely to interact and potentiate each other's influence.
Given that language and culture can influence effective strategies that improve medication adherence, such as patient education and communication [45], future studies should reinforce these by addressing language and cultural barriers in intervention studies.This will help create interventions that are more inclusive and effective for diverse patient populations.
The diversity of the strategies identified in the interventions reviewed aligns with the evidence from the literature, which suggests that a multifaceted approach is necessary to address medication adherence [27,28].Telephone and social media follow-ups have become increasingly popular cost-effective methods to maintain patient contact and provide ongoing support.For instance, a review by Cahaya and Skarayadi [46] showed a positive impact of eHealth on medication adherence in five studies and an insignificant impact in four studies.Thus, the effectiveness of strategies may vary depending on the context in which they are applied, underscoring the need for further research to identify the most useful strategies and corresponding settings.
To enhance the effectiveness of future studies targeting medication adherence in patients with both hypertension and diabetes, it is worth noting that most successful interventions in this review required continuous monitoring and engagement of pharmacists, which is not practical in routine clinical practice due to limited consultation time and a low clinician-to-patient ratio.To bridge this gap, other strategies can be considered, such as involvement of pharmacy technicians, community health workers (CHWs) or digital health innovations such as artificial intelligence (AI).Enhancing medication adherence through interprofessional collaboration between pharmacists and CHWs is proving to be a viable strategy.For instance, a study by Deidun et al. [47] reports on the use of Aboriginal CHWs to bridge the cultural gap between patients and pharmacists in a home medication review programme.Similarly, Wheat et al. [48] report on the development of a patient plan to   AI can be more widely incorporated into both monitoring and increasing medication adherence.For instance, a study that used AI to measure medication adherence, and provided medication reminders and dosing instructions, reported 100% adherence in the intervention group and 50% adherence in the control group [49].
Moreover, digital health tracking integrated with electronic health records can provide real-time data on medication adherence and send automated alerts to healthcare professionals when a certain level of medication non-adherence is detected.Although this proactive approach is promising, more research is needed to assess the long-term effectiveness of digital health-driven interventions in patients with coexisting hypertension and diabetes.

| Conclusion
The use of multifaceted interventions involving pharmacists and fostering continuous interaction between healthcare providers and patients has the potential to improve medication adherence in patients with both hypertension and diabetes.However, research on interventions targeting medication adherence in patients with both hypertension and diabetes is still sparse, making definitive conclusions challenging.
Multifaceted interventions effectively address the factors influencing medication adherence by incorporating both informational and sociobehavioural determinants of medication adherence.It is evident from the review that pharmacists have the potential to be good intervention initiators due to their opportunities to directly interact with patients and their expertise in pharmacotherapy and patient education.Continuous engagement between healthcare providers and patients allowed for proactive identification and resolution of barriers to medication adherence, leading to better treatment outcomes.
Data sharing is not applicable to this article as no new data were created or analysed in this study.

FIGURE 2 |
FIGURE 2 | Flow diagram of the study selection process.
adherence S-FBG, 2hPG, HbA1c, rate of reaching target BP and risk factor profile.

TABLE 1 |
Quality appraisal of included studies.

TABLE 2 |
Characteristics of included studies.

TABLE 3 |
Intervention characteristics and success.

TABLE 4 |
Additional outcomes assessed linked to hypertension and diabetes.